Administration of drugs by an oral inhalation route is very much in focus today, because of advantages offered like rapid and predictable onset of action, cost effectiveness and high level of comfort for the user. There are mainly two types of inhalers on the market, pressurized metered dose inhalers (pMDIs) comprising a suspension of fine medicament particles in a propellant gas and dry powder inhalers (DPIs) comprising fine medicament particles as dry powder.
Dry powder inhalers (DPI) attract perhaps the most interest, compared to pMDIs, because of the flexibility they offer in terms of nominal dose range i.e. the amount of active substance that can be administered in a single inhalation. So far most development efforts have been directed towards producing effective drugs and formulations for specific abnormal conditions and not so much towards developing the delivery device, i.e. the inhaler.
When inhaling a dose of dry medication powder it is important to obtain by mass a high fine particle fraction (FPF) of particles with an aerodynamic size preferably less than 5 μm in the inspiration air. The majority of larger particles does not follow the stream of air into the many bifurcations of the airways, but get stuck in the throat and upper airways. It is not uncommon for prior art inhalers to have an efficacy of 10-20% only, i.e. only 10-20% of the metered dose by mass is actually delivered as particles with an aerodynamic size less than 5 μm. Since most drugs have undesirable side effects and some may be quite toxic if overdosed, it is important to keep the dosing to the user as exact as possible and to design the delivery system, e.g. an inhaler, such that the efficacy becomes much higher than 10-20%, thereby reducing the required amount of drug in the dose. Also, depending on the targeted site of action, be it systemic or local in the throat and airways, it is desirable to tailor the physical formulation of a medication powder in such a way that it results in an advantageous particle aerodynamic size distribution by mass in the metered dose.
An interesting field of research concerns the possibility of simultaneous administration of combinations of different medicaments. Of course, it is well known in prior art that a successful treatment of a medical condition may is require administration of more than one active substance, e.g. a medicament for relaxing the immediate symptoms like pain or bronchoconstriction and another medicament for treating the underlying abnormal condition like systemic chemical imbalance or airway inflammation respectively. However, it is often difficult to mix the medicaments into a metered dose, because the medicaments may be known to be incompatible or else it is perhaps unknown if and how they interact before they are actually delivered to a subject Therefore, medicaments are generally administered separately, in sequence or by separate routes.
In the past decade research into respiratory diseases, their prophylaxis and treatment, has shown conclusively that simultaneous administration of combinations of different medicaments may improve the clinical condition of patients considerably. In Switzerland patients diagnosed with asthma have been prescribed FORADIL (formoterol, a bronchodilating substance) together with PULMICORT (budesonide, an anti-inflammatory steroid) since the 1980's for treatment of their asthma. Until recently, however, different asthma medicaments have generally been administered separately, in sequence or by separate routes, not in compositions comprising more than one active ingredient. However, there are several published patent applications and approved patents teaching methods of treating respiratory disorders like asthma and chronic obstructive pulmonary disease (COPD) and pharmacologic compositions of different biologic and chemical substances for this purpose, where the combinations offer overall advantages in the treatment of these conditions. See for instance EP 0416950B1 “Medicaments”, EP 0416951B1 “Medicaments comprising salmeterol and fluticasone”, EP 0613371B1 “New combination of formoterol and budesonid”, WO 98/15280 “New combination”, WO 00/48587 “Combinations of formoterol and fluticasone propionate for asthma”, WO 01/70198A1 “Stabilized dry powder formulations”, WO 01/78737A1 “Medical combinations comprising formoterol and budesonid”, WO 01/78745A1 “Medical combinations comprising formoterol and fluticasone propionate”, WO 02/28368A1 “New combination for the treatment of asthma”, WO 03/013547A1 “Pharmaceutical composition comprising salmeterol and budesonid for the treatment of respiratory disorders”. However, the quoted documents deal with aspects of formulating, processing, stabilizing and using mixtures of at least two ingredients. The chemical compositions and mixing ratios between active ingredients are generally focused upon, not methods of administration of such compositions or devices for that purpose. It is, however, difficult to mix dry medicament powders and optional excipients in a certain proportion consistently. The proportions in such a metered combined dose cannot be easily controlled, because the ratio of medicaments in an individual, combined dose depends significantly on the particle forces existing in each medicament powder, between particles of different medicaments and between medicament powders and dose packaging materials. Hence, actual variations in the ratio between active ingredients from combined dose to combined dose may be too large, causing serious problems if a potent ingredient is delivered in a higher or lower amount than expected.
Thus, there is room for improvements regarding methods and devices for simultaneous administration of different medicaments, which combine advantageously in treatment of certain medical disorders.